Spit It Out!

A patient perspective on developments in the treatment and management of Cystic Fibrosis. I'm a 39 year old living and working with CF and CF-related diabetes. Double F508del. FEV1 is currently 25%. My motto: "If it works, do more of it. If it doesn't work, don't do it. If you're not sure, do some experiments." Twitter: @oli_rayner

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Friday, 3 July 2015

Today the results of the UK CF
Gene Therapy Consortium’s Phase 2b clinical trial were published in Lancet
Respiratory Medicine. The trial achieved its primary endpoint by showing gene
therapy improves FEV1 in a statistically significant way. It is a big step
forward for CF science.

·The CF gene is
essentially an instruction to cells to produce a certain protein (CFTR) that is
needed to allow salt and water to pass across cell membranes. Without this
protein, airways and other important tubes get clogged with sticky mucus that
a) obstructs the tubes; and b) acts as a breeding ground for bugs. Researchers
are trying to find CF therapies to address the underlying defect at both the
gene and the protein level. There is also an intermediate step where the CF
gene produces a copy of itself (called RNA) and that copy is used by the cell
to manufacture the CFTR protein. Researchers are looking to design therapies
that work at the RNA-level too (e.g. ProQR).

·CFTR modulators like
Ivacaftor are thought to work by attaching to the defective CFTR protein and
encouraging it to work properly. They do not do anything at a genetic level. Since
different CF mutations mean different defects in the CFTR protein, CFTR
modulators are developed for specific mutations. This is one reason why they
are extremely high priced. Gene therapy works by putting a working copy of the
CFTR gene into cells so that the cells themselves produce normal CFTR protein (just
like someone who does not have CF) so the individual CF mutation is irrelevant.
This should also make the therapy more cost effective.

·It is hard to get
the gene therapy into the airways where it can actually work because the lungs
have evolved very effective self-defence mechanisms. Getting gene therapy into
the lungs means penetrating these natural defences as well as getting through all
the mucus that clogs the airways of people with CF. This needs to be done
without triggering an immune response that creates problems which outweigh
any benefit of the therapy. So the key challenges are delivery and safety.

·While gene therapy is
not yet a finished product and patients on the Phase 2b trial probably did not
feel major improvements in themselves, the results show that gene therapy can safely
deliver statistically significant treatment effects. Scientists think the
efficacy can be improved by increasing the dose/frequency of administration and
tweaking the vector (i.e. the design of the “missile” that delivers the gene
therapy “payload”). It is an important stepping stone in the development of
gene-based therapies that seek to correct the underlying defect and achieve a
functional cure for all CF mutations.

·The 3.7% difference
in mean relative % predicted FEV1 in the gene therapy group compared to placebo
is only slightly lower than that seen in the Phase 3 trials of
Lumacaftor/Ivacaftor in homozygous F508dels (4.3-6.7%).

·There was a wide
variation in response. The gene therapy benefited some much more than others
and it is not clear why.

·A wide range of
mutations were included in the trial and treatment effects were independent of
mutation.

·Those with more severe
disease (less than 70% FEV1) saw bigger effects but it is not clear why this is.
Intuitively, it makes sense that greater mucus obstruction in the smaller
airways of those with more sever disease would mean more drug dwelling in the
larger airways with a greater opportunity to act. It may also be harder to show
benefit in patients who are already relatively well.

·This trial has shown
repeat doses of gene therapy can be delivered into the lungs in a way that is
safe and produces benefits in terms of key health markers. Hopefully it will
give researchers and funders confidence to build on this work and explore the
potential to tweak the dose and/or the frequency of administration; develop
superior vectors; and also find an efficient way to test gene therapy in
combination with CFTR modulators like Ivacaftor.

·Further out, the
data should have positive implications for future iterations of gene therapy,
RNA-based therapies and gene editing approaches; and the UK GTC’s data,
know-how and experience is a community asset that will inform work in all these
areas.

·It is an exciting
time in CF because Ivacaftor has shown that, in certain mutations, the
functionality of the CFTR protein can be rescued and that, when this is done, people
with CF get a lot better. It has shown us what the destination looks like. However,
the recent results from Vertex’s Phase 3 trials of Lumacaftor and Ivacaftor in
combination for people with two copies of DF508del, the most common mutation,
show there is a long way to go before people with that mutation and other rarer
ones have a CFTR modulator therapy that does for them what Ivacaftor
monotherapy does for G551Ds. Even if they work, we may not be able to afford
them.

·While Ivacaftor for
G551Ds has set expectations sky high, in reality for most people alive today
with CF, stabilisation would be a very successful outcome. Stabilisation, if
maintained over a number of years (as compared to the standard annual 2-3%
decline), could mean that a person with CF takes, say, 60 years to get to the
point where they need a transplant rather than, say, 40 years and that is a big
deal – it could mean a very different kind of life for them and those around
them.

·For mutations which
are not responsive to Ivacaftor monotherapy, it is unlikely that a single pill
or other form of treatment will have all the answers. It is likely we will need
combinations of different forms of therapies (gene-based, RNA-based and
protein-based) working together and some form of gene therapy could be a
component of the overall solution.

·This trial and the
openness in relation to the data is a huge credit to the UK CF community and it
makes me proud to be part of it. While the Phase 2b trial itself was funded by
MRC/NIHR, a huge amount of work has taken place over the last 15 years to get
to this point and 90% of the overall funding has come directly from the UK CF
community. Indeed, it was the Cystic Fibrosis Trust that put the UK Gene
Therapy Consortium together in the first place. Adults with CF and parents of
children with CF have made this happen.

·It has cost around
£45m to get to this point. This is much less than the figures usually sited by
industry for getting through Phase 2.

·Patients from 18 UK hospitals
were able to take part in the trial. Not many hospitals have the facilities or
the capability to do trials like this but allowing local hospitals (acting as
“Patient Identification Centres”) to refer willing and eligible patients to one
of the two participating centres meant the trial could recruit to target and it
extended the opportunity to participate to a much wider group of patients.
There is going to be an increasing bottleneck in CF drug development as the big
CF centres are unable to cope with all the trials that will need to be done to
convert the pipeline and exciting science behind it into therapies for patients.
There is also an issue of equality of access to trials - it is not fair that
only patients at the big CF centres should have the opportunity to take part in
clinical trials. The Patient Identification Centre model, used for the first
time in the Phase 2b gene therapy trial, may be a way to address some of these
important issues.

Wednesday, 25 June 2014

Yesterday Vertex announced
preliminary results from the Phase 3 trial of Lumacaftor in combination with
Ivacaftor in patients aged 12 and over with two copies of the F508del mutation.
The trial involved 1,100 patients at almost 200 sites across the world.

For me, the most
interesting points were:

Mean absolute
change in % predicted FEV1 was approx. 3% and mean relative change in %
predicted FEV1 was approx. 5% (on the basis of pooled data). That means if a
patient’s baseline FEV1 was 60%, on average they would have seen an increase to
63%. While this is less dramatic than the effect seen in G551Ds on Ivacaftor
monotherapy, it was statistically significant and, for many people with CF,
each % point maintained is important;

Statistically
significant increase in Body Mass Index (BMI)

Delayed time
to first pulmonary exacerbation;

30-39%
reduction in pulmonary exacerbations (depending on the dose);

39-61%
reduction in exacerbations requiring hospitalisation;

45-56%
reduction in exacerbations requiring intravenous antibiotics;

Some people on
the trial had baseline FEV1 below 40%. While the eligibility criteria was 40%,
some dipped below this threshold in the period between screening and first
drug. These patients seem to have responded just as well as those with higher
baseline FEV1;

Approx. 90% of
people on the trial decided to rollover into the open label extension including
those who had been taking placebo during the trial period. This says something
about how the drug made patients feel in themselves; and

The Quality of
Life questionnaire (which is validated by regulators) failed to show any improvement
in quality of life. This seems at odds with the data above and, to me, suggests
the instrument is not tuned into the things that really matter to patients.
Perhaps there is a need to develop a new way of measuring quality of life. It
would be a long process to get a new instrument validated but it could pay
dividends and it something that could be done in partnership with patients and
families.

Vertex now plans to submit
the data by the end of 2014 to regulators in the US and EU in order to get a
marketing authorisation. If approval is given, they will then embark on the process
of securing reimbursement. All this will take time and there are risks at every
stage.

While this combination
therapy does not appear to be transformational for those with two copies of
F508del in the way Ivacaftor has been shown to be in many G551Ds, it is
exciting and provides a solid stepping stone for further development by Vertex
and others. It is probably more of a bridge to the future than a home run in
itself. It should reassure researchers that this problem is one that can be
solved.

It is surprising that the
effect on exacerbations was so dramatic given the modest effect on FEV1.

Here’s why I think reducing
exacerbations is more important than increasing FEV1:

FEV1 is hard to measure in
a reliable way even in adults. It is dependent on technique and it can be
affected by lots of factors unrelated to underlying lung function. It becomes
less reliable as lung function deteriorates which is, arguably, when we most
need a reliable measure.

If you ask someone with CF
how they feel, they are unlikely to talk about FEV1. FEV1 is not something patients
feel or necessarily perceive.

It is well established
that more exacerbations lead to worse health outcomes. The mechanism is clear
and cruel - most people with CF die of lung failure, every exacerbation can
cause incremental lung damage that is irreversible so moving us a little step
closer to lung failure. If we think of it like a staircase down to lung
failure, we obviously want the distance between each step to be as long as
possible and we want each step to be as shallow as possible. Weight gain
directly helps here too. Just breathing and keeping permanently resident bugs
at bay takes a lot of energy for us. The more energy we have in reserve the
better able we are to fight off infections before they flare-up into
exacerbations (or the better we are able to minimise the severity of the
exacerbations that do hit us). Therefore, weight gain can help extend the distance between steps and minimise the depth of the steps by creating resilience.

Obviously
exacerbations are disruptive to life so there is a clear and
immediate quality of life impact for patients and families.

Personally,
I wish I had known when I was younger that exacerbations tend to cause irreversible
lung damage and knock you down a step. When I was a teenager and relatively
healthy, I hated doing all my treatments particularly nebulisers and airway
clearance. I sometimes used to think, “I’m fine and busy with my life. I won’t
bother doing all my treatments. I'll wait until I get sick and then go to the
hospital to get fixed". I didn’t think I was losing anything but I really was.

Traditionally FEV1 is seen
as the gold standard test for measuring the effects of new therapies. There may
well be a case to review that now. The therapeutic pipeline for people with CF is
stronger than ever before and these results will help underpin further
development.

Monday, 10 March 2014

I have spent many hours researching travel insurance and travel oxygen. I just spoke to Insurance Choice and it feels like a breakthrough.

They are an arranger not an underwriter. She said the best underwriter by far for CF is "Fit for Travel". They are the only company who write their own medical questions and this makes them more flexible. She took my details and then went through their process with me. The questions were thorough but more sensible than normal. It seemed like they understand CF more than others!

They have a website but there's not much on it so I recommend just calling.

I have found in the past that the number of "unplanned" admissions I have had in the last year or two years has been a blocker. I usually go in 2 or 3 times a year. I go in when I am sick not a pre-planned basis. These guys ask about all admissions in the last two years (not just unplanned ones i.e. pre-emptive pre-planned ones count). In the last 2 years I have been in 5 times. This was not a blocker.

I also have CFRD and I need oxygen on the plane, with exercise and overnight. This was not a blocker.

I am thinking about going to Greece for 2 weeks in April. They quoted me £225. She said it would be similar anywhere in the EU.This includes £5,000 cancellation cover and £10m emergency including repatriation and legal.

After getting the quote, I had a decent chat with her. She said the question about admissions in the last two years has two answers "0-9" or "more than 9" i.e. if I had been in 9 times it would not make that much difference. If more than 9 admissions, they may still cover but it will cost more. She said she recently arranged cover for a lady with CF in a similar situation to me who is going to the US. The quote for her was £650.

I need to take oxygen abroad. I use 2 litres/min pulsed when I do exercise and I use 2 litres/min continous overnight. I will use 2 litres/min on the plan since the flight will be more than 2 hours. I tend not to need O2 for shorter flights. Air Liquide provide my O2 at home and they are pretty good about travel within the UK but they will not help abroad. If you have an EHIC you can arrange O2 locally within the EU but it can take a long time to organise, there is sometimes a cost and I'm told the equipment is not always as good as it is here. I called British Lung Foundation and they gave me a list of companies that will rent out portable O2 equipment to take abroad. This is going to cost me about about £400 for 2 weeks. I tried PureO2 (08707 120202), 10sMedical (0121 355 6555) and Intermedical (0800 0282194) and they are all similar but I would recommend PureO2 because they seem a little bit more professional and responsive. I can use this equipment on the plane too but if I go with an airline that provides it free I might use that facility.

The British Lung Foundation website is good for general information and the people on the helpline are very helpful:

Monday, 26 August 2013

A recent study sheds new light on which of the 1,900 plus known mutations of the CFTR gene actually cause cystic fibrosis (CF) and which do not. The study is called "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene" and it was published on 25 August 2013 in Nature Genetics. The results have important implications for family planning and drug development although this work is ongoing and part of a bigger project aiming to characterize all known CFTR mutations. Researchers analysed genetic information from nearly 40,000 CF patients to find out which of the 1,900 mutations cause CF and which are benign. Their findings increased the number of known CF-causing mutations from 22 to 127. Prior to this, more than 25% of couples in which both partners were found to carry a mutation on the CFTR gene could have no way of telling whether their mutations could actually cause CF in their offspring. As a result of this study, that is reduced to 9%. The work provides some interesting clues for drug development too. By looking at the differences in severity of disease caused by changes in CFTR associated with different genotypes, the researchers have a better idea of the potential efficacy of drugs which achieve the same changes in CFTR.I emailed some questions to Dr. Patrick Sosnay, co-author of the study and assistant professor of pulmonary and critical care at Johns Hopkins University.

How did
you do this study?

"We
collected CF patients and parents from around the world (mostly N. America and Europe) and
looked at the mutations they had. We then looked at each of these mutations to
tell for sure if they caused CF. We looked at the clinical outcomes of patients
that had those mutations (assuming the higher their sweat chloride, the more
likely the mutation was truly a CF causing mutation); we looked at how the
mutation behaved in experiments (the less it behaved like the non-mutated or
"wild-type" CFTR, the more likely it was truly a CF causing
mutation), and we looked at how often it was seen in people with CF, vs.
carriers, vs. the general population."

What is
the relevance of the results?

"We have
better defined the range that can be seen with the 159 most seen CF mutations. Some
always cause CF, some cause CF some of the time, and some we do not think cause
CF. Obviously, because it is a recessive disease a patient has to have
mutations on both copies of CFTR they inherit."

What are the
implications of this data for family planning?

"This will
help genetic counselling in that we will have a better idea what the most
likely consequence of a mutation is. People having genetic testing done before
this study were more likely to get back a CF mutation that we did not know how
to interpret. They would be told – you have a mutation in CFTR, we do not know
if it causes CF or not. There are still many mutations out there that are
uncharacterized, but we have chipped away at some of the more common ones."

What are
the implications of this data for drug development?

"This information
will be used by scientists studying therapies to group mutations according to
their functional consequences. We also hope to learn more about what contribution CFTR genotype makes to making CF mild or severe."

Monday, 29 April 2013

29 April 2013 at The Wellcome Trust, London."Good evening, everyone. It’s an
honour to be able to speak to you tonight. It’s a bit overwhelming actually. I
feel a bit like a kid speaking to a room full of Father Christmases.

I want you all to imagine – you can
close your eyes if you like - I want each of you to imagine you’re in a little
wooden boat floating in the middle of the ocean. As you bob up and down, you
feel the sun on your back, you can hear the distant sound of birds and you can
smell the sea air. Sounds pretty nice. But there’s a problem. The boat is full
of holes and water is gushing in. There are sharks. All you have (to bale out
the water) is a tea spoon. You spend most of your time baling with your tea
spoon trying to stay afloat. You do it all day. You go to sleep, you wake up in
a boat full of water and you start baling again. It is exhausting and
relentless. You need a bigger spoon. Better yet, you need to find a way to plug
the holes. That’s what CF feels like to me.
It’s a fight against drowning in my own mucus.

I was diagnosed in 1978 at the age of
3. When I was 14 my consultant told me I’d probably need a heart and lung
transplant in my early twenties and that I’d be lucky to live beyond 25. This
[Spoon 1] was standard of care in those days. Well my heart and lungs are still
original and I’m still here at 37. During that time, we’ve seen the development
of better spoons - nebulised antibiotics like TOBI [Spoon 2], mucus busting
therapies like Pulmozyme and Hypertonic Saline; and more effective airway
clearance techniques [Spoon 3]. These all resulted from research and I might
not be here without them. I want this [Spoon 4] but I have this [Spoon 3]. Kalydeco
is a bit different – it’s plugging holes - but I’ll come on to that.

New treatments are exciting and
important but, actually, I think it’s just as important to develop better tools
to manage symptoms and figure out how to use the tools we already have in a
more effective way.

So I want to talk about three things:
the therapeutic portfolio, clinical trials and adherence.

THERAPEUTIC
PORTFOLIO

Vertex’s new drug Kalydeco is a small
molecule with big implications. This little blue pill is changing the lives of
the 4% of CF patients with the G55-1D mutation. Trials to see if Kalydeco works
for other similar mutations are underway. Phase 2 data released by Vertex on
April 18th, in a press release, has bolstered hopes that Kalydeco might work in
combination with various other small molecules to treat a much broader range of
CF patients including people like me with the most common delta F508 mutation.

This is incredible – when I read the
blogs and hear the stories of people on Kalydeco – it is mind-blowing. It
brings a tear to my eye. But there’s a long way to go from Kalydeco to a
Kalydeco-like therapy for all 1,800 mutations and it is important to remember
that, even for G55-1Ds, Kalydeco is not a cure. These people still have CF.

They still need to do all their other
treatments. They still have chronic infections and exacerbations that mean they
need IVs - but not as often. They are significantly better, able to do more stuff
without getting breathless, put on proper weight, bounce back faster from
exacerbations and generally far more resilient. Those on Kalydeco seem able to
shake off a cold without it turning into an exacerbation – in other words two
weeks in hospital becomes 2 days off work. I hear about patients with G55-1D
who’ve come off the transplant list or who no longer need a wheelchair or
oxygen therapy. They can go back to work or perhaps go on holiday. Maybe their
parents no longer need to act as such full-time carers so they can go back to
work or have a more normal life too. These patients are able to think about and
plan for the future in an entirely new way. The trajectory of their disease has
changed. It is hard to explain because the way CF affects patients and families
is so complex - and maybe we need to find better ways of articulating the true value
of these medicines - but this is a profound leap forward and it is exciting to
think the same approach may help those with other mutations.

For young children whose lungs and
other organs are not yet damaged, drugs like Kalydeco could be very close to a
cure. For older ones whose organs have been damaged, Kalydeco might freeze the
disease but it won’t reverse damage already done. So even if there was a
Kalydeco-like treatment for all mutations, symptom-management tools will still
be needed. In fact, they may well be needed more than ever because people with
CF will be living longer.

CF is a complex disease and it seems
likely that complex combinations of small molecules and other kinds of therapies
will be needed. Lots of money is going into small molecule CFTR modulators. As
a patient, I worry we are putting all our eggs in one basket. It may not work.
It may half work. I think it’s vital for the CF community to nurture some
alternative approaches and facilitate some alternative science. I think we need
to hedge our bets.

The CF Trust has always been
committed to research and I think this commitment is more important now than
ever before. Of course, the Trust established and funded the Gene Therapy
Consortium and this is pioneering new techniques. While even this is not a “cure”
as such it may turn out to be just as important as small molecules or more
important. This would not have been possible without the Trust’s funding and the
tenacity of those involved. I hope the Trust can continue to support this
programme as part of a broader portfolio.

It’s essential that the CF Trust
works in conjunction with the CF Foundation and others to achieve a diversified
portfolio of therapeutic options. We need to go after better spoons - more
effective symptom-management tools (particularly those which can reduce
inflammation or neutralise Pseudomonas and other lethal bugs) – as well as
looking for new ways to rescue chloride channel function - to plug the holes.

CLINICAL
TRIALS

In the UK, about 10% of CF patients
have participated in a clinical trial. We need to do more. We make it far too
difficult for sponsors to do trials. We need to make it easier because we’re
all losing out.

Studies show that simply taking part
in a trial can improve a patient’s health and that is irrespective of whether
they receive the active drug or placebo; and irrespective of whether the trial
has a positive or a negative result. It is not just about being an altruistic
guinea pig, it’s about direct benefits (for patients, clinicians and hospitals)
and establishing a more positive culture that forces everyone to raise their
game and not to settle.

This means making sure that, when
there is a new drug, our patients have the opportunity to take part in clinical
trials but it also means doing more trials to make sure we are using the tools
we already have as effectively as we can.

Trials, funded by the CF Trust, like
the TOPIC study on once vs three times a day aminoglycosides, have resulted in
significant improvements in care. In some cases they have allowed treatments to
be simplified and ineffective ones to be stopped. These kinds of trials are really important and we need to do
more.

It also makes sense to get patients
and parents involved in clinical research at the design stage. After all,
clinicians only see patients and collect data when the patient comes to the
clinic - or in hospital. It is the patients and their families who live with CF
day-in/day-out. We are the only ones with a 360 degree view. Why can’t we use
this experience, and data collected at home, systematically to inform clinical
trials, and clinical practice more generally, to make sure we’re asking the right questions and working towards the
outcomes that are most relevant to patients in their daily lives? Internet
technology has made this easy to do and, if our aim is to improve real world
outcomes, I think we have no choice but to embrace it. That’s why I’m really excited
by initiatives like CFUnite (backed by The Wellcome Trust), Cochrane and the
James Lind Alliance; and the CF Trust’s commitment today to do more to facilitate
patient involvement in this more strategic aspect of clinical trials.

ADHERENCE

This is a big deal and we need to
talk about it more. One of the most challenging aspects of having CF, for me,
is the heavy burden of daily treatment. Every day I take about 40 pills, 7
nebulisers, a saline nasal rinse, 4 inhalers and do 2 or 3 injections, blood
sugar tests and two sessions of self-administered physio. I spend a lot of time
washing and sterilising nebuliser equipment. All this takes 3 hours on a good
day and up to 4 hours when I am less well. This is my normal. When I get an
exacerbation I typically need a 14 day course of hospitalised IV antibiotics. This
tends to happen 2 or 3 times a year. I am lucky, for many it is much worse.

So CF adherence is not just popping
pills - this is real work, it is difficult and it can be exhausting. You can
never take a day off. Some of the treatments are unpleasant - they require a
lot of effort and willpower. It becomes much harder to get all your treatments
done, and it takes longer, when you’re not feeling so well which is, of course,
exactly when you need them most. It is easy to feel overwhelmed with
treatments. It’s hard to find a balance. It is hard to create reliable windows
for work, family and friends; and for all the other things you have to do to
get by in life.

So we need to find ways to reduce the
burden of treatment. Something which saves an hour a day and can be done
anywhere is going to have a dramatic impact on quality of life and, I think,
adherence. Clearly there is a link between poor adherence and hospitalisation.
We do too much fire-fighting and we need to focus more on prevention. We need
to recognise the value of prevention.

It may mean simplifying treatments;
developing a pill or inhaler to replace a nebuliser (more things like
Bronchitol, TOBI Podhaler and Colobreathe); or more creative things, perhaps
bringing in some sports psychology techniques; or web-based platforms or smartphone
apps that help to manage and motivate or allow people to track their progress
or even just talk to someone who’s in the same situation (because don’t forget
we can’t meet up due to the risk of cross-infection). This kind of thing could
help people live a fuller life, stay healthier, reduce exacerbations and keep
them out of hospital. This is worth doing, big time, and I think it’s great
that the Trust has highlighted adherence and reducing the overall burden of
treatment as key research priorities. It’s a simple relation: reduce the
burden, improve adherence; reduce exacerbations.

So here’s what I want you to take
away:

The CF Foundation and Vertex have
blazed a regulatory trail, given us new tools, shown Pharma that CF is a real
market, shown everyone what can be achieved when Pharma works with a patient
group. They have delivered a transformative drug for a very small
sub-population of CF. I see this as injecting oxygen into the CF research environment.
It’s woken people up. It’s like our Big Bang. We need to capitalise. We need to
use it to our advantage. That’s why the Trust’s new strategy launch is
perfectly timed. It provides
a great scientific map but it also sends a clear signal of the Trust’s intent
to collaborate with new partners, in new ways and to make resources available to
help everyone in the CF community convert their ideas into new therapeutic
tools.

Saturday, 2 March 2013

Last week I was invited by Yann Le Cam, CEO of EURORDIS, to some important rare
disease policy events in Brussels. These events brought together a very
passionate community of people including EC officials, MEPs, representatives
from the European Medicines Agency, national officials, Pharma, researchers,
patient groups and others. All these people are working on ways to improve
access to orphan medicines and better treatment options for people in the EU
with rare diseases. I was really impressed with the way people from
across the spectrum were all working together and making a difference. It felt
like there was a great sense of camaraderie and real solidarity with everyone
uniting against "the system" which I found surprising and
inspiring. I found the experience genuinely moving and it was great to
have the chance to meet so many smart people working in such an important and
relevant area.

Based on my recent experience of the issues with getting Vertex’s
Kalydeco to patients in need, I was keen to go along and find out what is being
done at the EU level to address some of the problems. As I see it, there are
problems at almost every point of the drug development cycle from clinical
trial design and marketing authorisation through to payers' cost-effectiveness
reviews and post-marketing data collection.

Why does it take so long after EMA Marketing Authorisation for drugs
to reach patients? Why aren’t new treatments compared to current standard of
care? Why wasn’t Bronchitol tested against hypertonic saline? Why do regulators
insist new antibiotics are tested against placebo when hardly anyone with CF is
not on at least one antibiotic? Why don’t NICE and other payers take proper
account of quality of life, adherence and the effects of a new treatment on
patients’ family members? Why don’t people get angry about their governments
wasting hundreds of millions on branded drugs when therapeutically-equivalent,
lower-cost generics will do the same job? Why do people object to paying high
prices for genuine innovation? Why does it cost so much to bring a new medicine
to market? These sorts of issues are common to all rare diseases and we stand a
better chance of changing things if Pharma, patient groups, clinicians and
others work together as everyone’s interest is served by improving access to rare
disease medicines and the real problem is often government or State-controlled
healthcare providers and health insurance systems.

A rare disease is any disease that affects a small percentage of the
population. The European Union considers a disease as rare when it affects
fewer than 1 in 2,000 citizens. Rare diseases are frequently chronic,
progressive, degenerative and often life-threatening. Over 6,000 different rare
diseases have been identified to date and 30 million people in Europe are
affected. Rare diseases are also known as orphan diseases because they have
traditionally been abandoned by governments and drug companies who cannot
justify the investment in researching new treatments for such small groups of
people. Despite their vast overall number, rare disease patients frequently
lack access to diagnosis, treatment and the benefits of research.

EURORDIS is a non-governmental patient-driven alliance of patient
organisations and individuals active in the field of rare diseases, dedicated
to improving the quality of life of all people living with rare diseases in
Europe. EURORDIS represents 561 rare disease organisations in 51 countries
(including 25 EU Member States) covering more than 4,000 rare diseases.

In terms of EU rare disease policy, EURORDIS is clearly the prime
mover and they have built a collaborative community of key stakeholders to
shape and implement policy at the highest level. Yann Le Cam and his team have
built this community and really drive it forward in a way that benefits
patients while keeping key stakeholders on board. That is a wonderful thing. Overall
I had a fascinating time over the Tuesday and Wednesday in Brussels and I hope
to be able to build on my relationship with EURORDIS and the rare disease
community as a whole.

The Big Picture

There seems to be a realisation, in this community at least, that science
is progressing in such a way that medicine is increasingly able to address
whole new areas of disease and treatments are becoming more personalised. Treatments
which only work on a small number of people are very expensive. We are moving
into a world of ultra-orphan indications. It is clear that we will not be able
to afford to pay for everything. So everyone is thinking very hard about what
is funded and how to change the way the system is funded to maximise the
benefit. In particular, there is increasing concern about the fact healthcare
in the EU is largely “pay-as-you-go”/ unfunded in contrast to pensions which
are generally funded, albeit poorly. Economists all agree that healthcare
spending is going to become a far more significant proportion of total public
expenditure in the future. Social/welfare commitments are seen as fundamental
to the EU model so we had better find a way of paying for it! There is an
increasing realisation that better healthcare would allow people to work more
and for longer so spending in health will take pressure off social/welfare
budgets. There should be more “fluidity” between health and welfare budgets.
People, in this community at least, are starting to think about this in a more
integrated way.

It turns out that Pharma may be prepared to negotiate caps on general
pharmaceutical budgets if it means more spending on orphan products. This is
seen as a “re-distribution towards innovation” and something to be
welcomed. Similarly, everyone involved
in the rare disease community should help to identify and highlight
inefficiencies / waste in healthcare systems so as to force their governments
to make savings where possible and create a greater degree of “headroom for
innovation”.

There was a lot of talk of the need to mobilise “civil society” to
force change. While EURORDIS is seen as a very effective voice for rare
diseases in the Brussels village, there is an urgent requirement to mobilise
local patient groups and other grass roots activity.

This measure aims to speed up the process of Health Technology
Assessments and Pricing and Reimbursement decisions. It aims to remove duplication
of work between the EMA and HTAs in individual countries and to bring greater
transparency.

There is already a transparency directive in place but it is “soft” and
poorly implemented and it is no longer compatible with the dynamics of the
pharmaceutical market, particularly in relation to generics. The “new” Transparency
Directive aims to bring greater transparency to the Pricing & Reimbursement
(“P&R”) procedures in each Member State (e.g. the HTA reviews carried out
by groups equivalent to NICE). According to EU officials, it is widely known
that officials in several Member States are currently bribed to delay the entry
of generics. A major objective is to stamp out corruption and save money for
payers, particularly by accelerating generic substitution. It is estimated that “late” transition to
generics costs the EU more than €1bn per annum. Saving money for healthcare
budgets in this way would release funds for the more expensive orphan drugs
that will be an increasing feature of the market going forward.

The three elements are:

1. Time Limits: 180 days hard deadline for all P&R decisions but
much shorter (30 days) for generics;

2. Statement of Reasons: national authorities must provide verifiable
grounds for decisions; and

3. Remedies: legal remedies to be made available to applicants in the
event of adverse decision.

The Directive also seeks to bring a clear separation of the Marketing
Authorisation (MA) process and P&R processes in Member States and to
eliminate duplication of work as far as possible given the fundamental rights
of Member States to organise and fund their own healthcare systems (Article
168/7 Treaty on the Functioning of the European Union). The Directive aims to
stop competent authorities in Member States from re-assessing aspects that have
already been thoroughly assessed by the EMA as part of the MA process; to stop
them “re-opening the science” or even re-evaluating the orphan designation.

Richard BergstrÖm,
Director General of the European Federation of Pharmaceutical Industries and
Associations (EFPIA) talked about how the pharma market had changed.
Traditionally, pharma would consider their job done when their products got MA.
Now there is a “4th hurdle” – the Pricing & Reimbursement
hurdle. The real issue at the moment is access to medicines and that means who
is going to pay, how much and when. The Transparency Directive is a necessary
and important technical/procedural measure but it does not address the key
issue. He said the current system in the EU is a mess and it doesn’t work for
patients, payers or Pharma. It is too fragmented and this makes it very
difficult for pharma. Pharma is open to talking about price and doing deals but
there is currently nobody to call. For regulatory matters it is easy, you just
go to the EMA. For P&R matters, there is no place to go. There needs to be
a “front door” where people can go and have a sensible discussion.

It was great to listen to Richard BergstrÖm talk. He has an ability to cut
through the procedural language and bureaucratic obstacles to get to the big
issues, join all the dots together and say what really matters. It is incredibly
refreshing to hear such integrated thinking and, as a patient, I found it
extremely encouraging. It is mad that you get labelled as a shill for the Pharma
industry if you criticise government and market inefficiency when in fact your only objective is to get medicines to patients faster and encourage Pharma
to take the risk of developing new treatments. The media in the UK is extremely
"tabloid" in its approach to these issues and it is very unhelpful. I always feel politicians
try to deflect attention from their own failings by seeking to paint Pharma as the bad guys
and the media lap this up as it plays so neatly into the anti-capitalist
narrative. Why don't people get more angry about their governments wasting hundreds of
millions of Euros on branded drugs when generics will do just as well? Yet we balk at paying a decent price for genuine innovation (even though the total
amounts represent a fraction of the wastage elsewhere). BergstrÖm made a strong point when
he said society wanted a "tap" of new drugs but they did not want to
pay for the pipeline to supply the tap. I got a powerful sense that BergstrÖm is an agent for positive change and I wish there were more people like him.

Antonyia Parvanova, the brilliant outspoken MEP who is sponsoring the
Transparency Directive and Cristian Busoi MEP who is also instrumental in this
legislation, talked about an ambition to build a common market in
pharmaceutical products - it is not one of the product categories for which a
common market has been established under EU law. They see the Transparency Directive as
critical to bringing clarity and transparency to the HTA/reimbursement process,
eliminating corruption and saving substantial amounts of money by accelerating
the transition to generics and getting new medicines to market faster.

The emphasis is on showing the value / savings available to all
parties rather than sanctions. Payers will save substantial amounts of money,
pharma will be better able to invest and patients will get better access to treatments.

There is a great deal of work going on around the total burden of rare
diseases (i.e. health, welfare and social costs) so that we can see the true
value of new medicines.

In terms of broader EC policy, Jaroslaw Waligora (Policy Officer, DG Health
and Consumers) talked about the importance of patient registries in rare
diseases. These are seen as crucial to effective research going forward.
Currently there are hundreds of separate rare disease registries around the EU,
not compatible with each other and hard to access. They need to be easier to
aggregate and analyse. There are some initiatives that are helping (e.g.
EPIRAR, EJA Joint Action, RD Connect) and there is a new EC initiative to
establish a common platform (IT tools, software). This aims to bring greater
compatibility, enable better data analysis and facilitate clinical trials. The
disease-specific “European Reference Networks” made up of “Centres of
Expertise” are an important part of this too.

Several audience members raised concerns about the Data Protection
Directive and made the point that it raises barriers to patient registries
which are so crucial to rare disease research. EURORDIS has released a clear
statement on this issue (in defence of patient registries) and others with an
interest in rare disease research should voice their concerns too. This issue is
particularly important to CF and if patient registries are made impossible to
operate as a result of the Data Protection Directive, as proposed, it will be a
serious barrier to the development of new treatments.

There were about 100 people in the room including EC officials, MEPs,
other officials from Member States, people from EMA, Eurordis, Pharma,
Researchers and Patient Groups. The meeting was broadcast live over the web.

EURORDIS “Black Pearl” Gala
Dinner 2013

This was a fundraising event with around 300 people in attendance. The
aim was to explain the achievements to date of EURORDIS and the rare disease
community but also to highlight the massive challenges ahead and the need for
greater cross-border co-operation. They played some incredibly moving videos
showing real life stories of people with rare diseases. Awards were presented
to certain individuals and companies who had made a significant difference to
the lives of those with rare diseases.

I sat next to the wonderful Avril Daly who is a Board Member of EURORDIS,
Head of Public Affairs for the Irish Charity Fighting Blindness and a leading
figure in the Irish rare disease community. We talked about CF in Ireland and
the work of EURORDIS. Avril’s energy and commitment is incredible and she is a
true inspiration. Others on my table were Ken O’Reilly and others from Biogen
Idec and Axel Van Der Mersch who is a major funder of EURORDIS.

Adaptive/Progressive Licensing:
the idea that you could start off with a licence in respect of a small
population after a small trial but then gather more data and do progressively
larger studies to build the evidence base and get a progressively broader
licence over time. This would mean a constant cycle of data and a need for
regulators and payers to become more comfortable making decisions on less
evidence (at least initially)

The two key initiatives being sponsored by the European Commission,
namely CAVOMP and MOCA, are designed to improve access to
orphan medicines and treatments for rare diseases. The emphasis is on creating
a more efficient market and creating real value for all parties rather than
thinking about the issues in terms of Corporate Social Responsibility which has
been shown to be ineffective.

This is essentially a proposed methodology for removing duplication of
work and sharing information more effectively (among regulators, national
competent authorities, HTAs, payers, patient groups, clinicians, et al.)
through the whole lifecycle of a new drug (Orphan Designation – Protocol
Assistance – CHMP Opinion – Marketing Authorisation – HTA – Reimbursement). A
key part of this is a permanent co-operation mechanism for HTAs building on the
EUnetHTA. EUnetHTA is a network of government appointed organisations (from EU
Member States, EEA and Accession countries) and a large number of relevant
regional agencies and non-for-profit organisations that produce or contribute
to HTA in Europe. See: http://www.eunethta.eu/.

EUCERD made a formal recommendation to the EC in September 2012 and
the EC is considering how to implement it and incorporate it into future policy.

“MOCA”: Mechanism of
Coordinated Access to Orphan Medicinal Products

The objective of this work is to find common, non-regulatory
approaches to ensure better, timely and equitable access to orphan medicines
after their marketing authorisation.

A key aspect is better identifying the true value of new orphan drugs
and moving to a pricing system based on value rather than cost. While it is
acknowledged that payers will want visibility on cost construction as a quid
pro quo for market exclusivity, there is a need to move towards a more rational
value-based approach. This is called the Transparent Value Framework (“TVF”).

I took part in a "breakout” session to talk about this and I raised
some points about the burden of treatment in diseases like CF: a) that new
treatments which reduce the burden of treatment and which are likely to have a
positive impact on adherence (with potential associated savings for payers)
should be valued more highly; and (b) that it is important for clinical trials
to be designed in a way that provides HTA’s (and clinicians/patients) with the
information they need to assess the benefits of new treatments in comparison to
current standard of care as it exists in reality rather than as perceived by
the FDA / EMA. These points were well received, people felt they were relevant
to rare diseases generally and a number of people came up to me afterwards to say
what a useful discussion it was and that they were keen to talk more.

The final report is due in March 2013 and the EC will
consider how best to implement the proposals and how to factor them into future
policy.

Research also shows a great inequality of access to medicines amongst
Member States (particularly in the countries suffering financial hardship) and
major inequalities in pricing. For example, the Czech Republic pays more for
medicines than the UK. As a result of
“reference pricing” where certain countries in the EU insist on paying the same
as certain other countries in the EU system (even if they are in financial
distress and benefiting from special deals with Pharma), there is now a
tendency for Pharma to refuse to supply certain markets so as to protect
pricing power in other more important markets. There are discussions going on
as part of the MOCA process around mechanisms to improve equality in these
areas. “Differential Pricing” is seen by all (including Pharma) as a viable option.
This would involve countries in the EU with lower GDP/capita being charged
lower prices.

The other topic of the day was “National Measures”. Each Member State
has been told to develop a national plan for the treatment of rare diseases and
this includes improving access to new orphan medicines. A few countries have
implemented their plans, notably France, some have developed but not yet
implemented (e.g. UK) and others are still developing.

Another topic discussed at various points was the concept of the
“right to reimbursement” and free movement within the EU. In other words, rare
disease patients resident in one country should be free to travel to other
countries in the EU and be entitled to the same level of treatment. This is
seen as an important long term objective. There are increasingly cases of
people travelling or even moving to places where they can get treatment which
is not available in their home markets and even cases where parents of children
with rare diseases cannot afford to move to a new country so they put the child
up for adoption to go to families living in countries where treatment is
available. France absorbs a lot of patients in this way and it is seen as a
major issue in terms of equality and sustainability.

Eurordis will be making all the presentations and
other materials available on their website in due course. A huge amount of
ground was covered in much more detail than I go into here but I hope this gives
a flavour of everything.

This is a great community of people. I had expected
it to be a lot of hot air and grand talk of unrealistic ambitions but I was
surprised at the level of camaraderie and the way people were cutting through
to practical issues. It was also very striking how everyone from the EC, MEPs,
Pharma and Patient Groups were genuinely collaborating with a shared goal of
getting medicines to patients faster. It was quite inspiring and definitely
something to build on.

In addition to the brilliant team at EURORDIS, I met
people from the European Commission, European Medicines Agency’s Committee for
Orphan Medicinal Products, Fighting Blindness, Alliances Maladies Rare, the European
Network for Ichthyosis, the Belgian National Health Insurance System and the
following Pharma companies: PTC Therapeutics, Pfizer, Genzyme, BioMarin Europe,
Bioden Idec and Celgene.

I attended these events as a representative of the CF Trust and I
would like to thank them for part-funding my trip.

About Me

I was diagnosed with CF in 1978 at the age of 3. After graduating from UCL with a law degree in 1998, I spent 12 years working in investment banking and private equity in London. I now work for myself. I am currently working with the Cystic Fibrosis Trust as a Special Adviser on Research and Patient Involvement; I am also a director of Zespa Media, an independent TV production company and a consultant to Asset Match, an online peer-to-peer platform for trading shares in UK private companies. In addition, I am a consumer reviewer for Cochrane’s Cystic Fibrosis & Genetic Disorders Group and I write a regular column on CF research and the drug development pipeline for CFUnite.org, backed by The Wellcome Trust.